Esters derived from (RR,SS)-2-hydroxybenzoate of 3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl

ABSTRACT

New esters derived from (RR, SS)-3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl 2-hydroxybenzoate, analog to Tramadol, a process for obtaining them and the use of these compounds for the production of a medicament with analgesic properties. 
     These new products of general formula (I) exhibit an analgesic activity higher than that of tramadol.

This application is a 371 of PCT/ES00/004896 filed Dec. 26, 2000.

FIELD OF THE INVENTION

The present invention refers to new esters derived from (RR,SS)-3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl2-hydroxybenzoate, analog to Tramadol. The obtained compounds exhibit ananalgesic activity higher than that of tramadol.

BACKGROUND OF THE INVENTION

Treatment of pain is of foremost importance in the field of medicine.The pharmacological agents currently used for the treatment of pain maybe included, for the most part, in two large groups: opioid compoundsand nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAIDs are onlyuseful in the case of light to moderate pain; severe pain has beentraditionally treated with opioid compounds. However, said opioidcompounds present a series of undesired side effects, such asconstipation, respiratory depression, and tolerance and addictionliability.

U.S. Pat. No. 3,652,589 describes a class of analgesic compounds with astructure of substituted cycloalkanol phenol ethers having an aminogroup of alkaline character in the cycloalkyl ring. Among them, thecompound (1R,2R or1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol,commonly known as Tramadol, may be thrown into relief, and it isspecifically claimed in said patent.

Tramadol

A series of products derived from the previous ones, in whichdehydration in the cycloalkanol ring together with demethylation of the3-methoxyl on the phenyl ring has taken place, having the structure:

are disclosed in the Dutch Patent NL 6,610,022.

This patent also describes products derived from those of theaforementioned US Patent, in which the methoxyl group at the 3-positionon the phenyl ring has been demethylated. Namely, products having thestructure:

Among the products described in this patent O-demethyltramadol isincluded, which compound has been described as one of the metabolizationproducts of Tramadol (Von W. Lintz and col. Arzneim-Forsch (Drug Res) 31(II); 1932-43 (1981). To its (+) isomer has been attributed theanalgesic activity of Tramadol (Lars Poulsen and col. Clin. Pharmacol.Ther (St. Louis) 1996, 60 (6), 636-644). Even so, data do not exist onthe clinical use of the metabolite O-demethyltramadol.

More recently, in EP 753506, new O-demethylsubstituted, 1-halogenatedand/or 3-cyclohexyl substituted derivates of tramadol, have beendescribed.

Tramadol possesses an opioid agonistic effect. However, the clinicalpractice with Tramadol indicates that in spite of this fact, it does notpossess some of the typical side effects of the opioid agonists, such asrespiratory depression (W. Vogel and col. Arzneim. Forsch (Drug Res) 28(I), 183 (1978)), constipation (I. Arend and col., Arzneim. Forsch (DrugRes) 28 (I), 199 (1978), tolerance (L. Flohe et al., Arzneim. Forsch(Drug Res) 28 (I), 213 (1978)) and possibility of abuse (T. Yenagita etal., Arzneim. Forsch (Drug Res) 28 (I), 158 (1978)). Some specific sideeffects of Tramadol, caused when it is rapidly injected by theintravenous route (i.v.), such as suffocations and sweating, have beendetected.

Another of the drawbacks shown by Tramadol is its short duration ofaction (T. Matthiesen, T. Wohrmann, T. P. Coogan, H. Uragg. “Theexperimental toxicology of tramadol: an overview”. Toxicology Letters,95, 63-71, (1998)).

Because of the previous backgrounds, new compounds with an improvedanalgesic activity still are of interest.

DESCRIPTION OF THE INVENTION

The present invention refers to new derivates of(RR,SS)-3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl2-hydroxybenzoate, analog to Tramadol.

The analgesic activity of these compounds has turned out to be higherthan that of Tramadol.

In particular, the present invention describes and claims the productsof the general formula (I), their salts and optical isomers, as well asa process for the preparation thereof. The present invention also refersto the use of these compounds for the production of a medicamentintended for treatment of pain.

The products of the present invention are represented by the followinggeneral formula (I):

wherein:

-   -   R₁ is halogen, optionally substituted C₁-C₆ alkyl, OR₃, NO₂ or        optionally substituted aryl, where R₃ is C₁-C₆ alkyl.    -   R₂ is H or CH₃CO—.

Preferably, R₁ is halogen, such as F, Cl, Br, halosubstituted phenyl, orhydro(C₁-C₆ fluoroakyl).

Particularly, the preferred compounds of the present invention are:

-   (RR-SS)-2-Acetoxy-4-trifluoromethyl-benzoic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester-   (RR-SS)-2-Hydroxy-4-trifluoromethyl-benzoic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester-   (RR-SS)-4-Chloro-2-hydroxy-benzoic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester-   (RR-SS)-2-Hydroxy-4-methyl-benzoic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester-   (RR-SS)-2-Hydroxy-4-methoxy-benzoic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester-   (RR-SS)-2-Hydroxy-5-nitro-benzoic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester-   (RR-SS)-2′,4′-Difluoro-3-hydroxy-biphenyl-4-carboxylic acid    3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

The compounds of general formula (I) may be obtained by means of thefollowing procedures, also within the scope of the present invention.

DESCRIPTION OF THE METHODS

Method A

The compounds of general formula (I) of the present invention may beobtained by means of a general procedure characterized in reacting acompound of the formula (II) with the corresponding acid or acidderivate of the general formula (III):

wherein R₁ and R₂ have the above defined meaning, and

-   L=OH, halogen,    O—R₄ or —CO—R₅,    where-   R₄=C₁-C₆ alkyl, phenyl, optionally substituted phenyl, and-   R₅ Alkyl, a phenyl ring optionally substituted with one or more    substituents, or a heterocyclic ring optionally substituted with one    or more substituents.

Preferably, L is OH or halogen.

The reaction is carried out in an inert solvent, such asdichloromethane, tetrahydrofuran, acetonitrile, 1,2-dichloroethane,ethyl acetate, dimethoxyethane or dioxane, preferably dichloromethane ortetrahydrofuran, at temperatures ranging from −20° C. to 120° C.,preferably from 0° C. to 35° C., to obtain compounds of higher purity,and preferably in the presence of a condensation promoting agent toaccelerate the reaction, such as carbonyldiimidazole,dicyclohexylcarbodiimide, triethylamine ethylchloroformate,triethylamine benzotriazoletosylate or diethylchlorophosphate,preferably carbonyldiimidazole or dicyclohexylcarbodiimide.

The compounds of formula (II) are obtained according to the methodsdescribed in the literature (NL 6610022 or Flick et al., Arzneim.Forsch/Drug Res. (1978), 28 (I), 107-113).

Method B

This method consists in subjecting a compound of general formula (Ia)wherein R₂=CH₃CO to a hydrolysis reaction in an acidic medium to obtaina compound of general formula (Ib) in which R₂=H:

wherein R₁ has the above defined meaning.

Next, the methods used for ascertaining the pharmacological activity ofthe compounds are described.

Analgesic Activity Assays

Hot-Plate Method

The method used is the one described by Eddy N. B. and Leimbach D. (J.Pharm. Exp. Ther. 107: 385-393, 1953). The analgesic effect of theproducts was assessed by analyzing the behavior of animals on a hotsurface maintained at 55° C.±1° C.

Male Swiss mice weighing 20-25 g were used. The test compounds wereadministered, by the oral route, 1 hour before beginning the test.

The method consisted in placing the animals on a hot plate, whilemaintaining them in a 25 cm diameter and 21 cm height Plexiglascylinder, and determining the time that they take in jumping off the hotsurface. The animals were selected before the beginning of the test sothat those animals that remained more than 10 seconds without jumpingwere not included in the group that would receive treatment.

After the administration of the product under study, the test wasrepeated, the maximal permanence time on the hot plate being measuredyet again. Those animals that did not jump lapsed 60 seconds wereremoved from the plate in order to avoid damage to the animal, and theywere taken as being 100% protected.

The results were expressed as percent increment in the time (t) of jump,which was calculated as follows:${10\%\quad{{increm}.\quad t}\quad{jump}} = {\frac{\left( {{t\quad{jump}\quad{treated}} - {t\quad{jump}\quad{basal}}} \right)}{t\quad{jump}\quad{basal}} \times 100}$

It is an object of the present invention the use of the compound of thegeneral formula (I) for the production of a medicament intended for thetreatment of pain. Likewise, it is also an object of the presentinvention a pharmaceutical composition, which comprises said compound ofthe general formula (I) together with a pharmaceutically acceptableexcipient, for the treatment of pain.

EXPERIMENTAL

Next, the following illustrative examples are set forth, but they arenot to be construed as limitative of the scope of the invention:

SYNTHESIS EXAMPLES Example No. 1(RR-SS)-2-Acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl Ester

To a solution of 15.0 g (60.5 mmol) 4-trifluoromethylacetylsalicylicacid in 150 ml anhydrous tetrahydrofuran 9.3 g (57.4 mmol)carbonyldiimidazole was added, at room temperature, under an inertatmosphere. After thirty minutes, 13.1 g (52.6 mmol)3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol was added. Theresulting solution was maintained at room temperature for 3 days. Themixture was added onto a NaHCO₃ aqueous solution at pH 8 and it wasextracted with dichloromethane (3×50 ml). The pooled organic extractswere dried over Na₂SO₄, filtered and concentrated at reduced pressure togive a residue which was purified by column chromatography on silica gel(eluent: 9:1 dichloromethane/acetone and increasing amounts of acetone),whereby yielding 20 g of the title compound as an oil.

¹H-NMR (CDCl₃): 1.20-2.25 (m, 16H) including a 2.15 (s, 6H); 2.30 (s,3H), 2.45 (dd, 1H); 7.08 (m, 1H); 7.15-7.50 (m, 5H); 8.35 (m, 1H).

Example No. 2 (RR-SS)-2-Hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

The compound of Example 1 was dissolved in 600 ml isopropanol and 25 ml35% hydrochloric acid. The resulting solution was stirred for 16 hoursat 40° C. The isopropanol was evaporated, the residue was dissolved in100 ml dichloromethane, and it was added onto 100 ml of a NaHCO₃ aqueoussolution at pH 8. Extraction of the product was carried out, and theaqueous phase was washed with fresh dichloromethane portions (2×50 ml).The pooled organic extracts were dried over Na₂SO₄, then filtered andconcentrated at reduced pressure. The resultant crude product waspurified by column chromatography on silica gel (eluent:dichloromethane/acetone 9:1 and increasing amounts of acetone), whereby12.4 g (57%) of the title compound were obtained as a white foam.¹H-NMR(CDCl₃): 1.20-2.30 (m, 16H) including a 2.15 (s, 6H); 2.45 (dd,1H); 7.08 (m, 1H); 7.15-7.35 (m, 2H); 7.45 (m, 3H); 8.20 (m, 1H); 10.50(br. s, 1H).

Example No. 3 (RR-SS)-4-Chloro-2-hydroxy-benzoic acid3-(2dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

To a solution of 10.0 g (58.0 mmol) 4-chlorosalicylic acid in 150 mlanhydrous tetrahydrofuran 8.9 g (54.9 mmol) carbonyldiimidazole wasadded at room temperature and under an inert atmosphere. After thirtyminutes, 12.6 g (50.6 mmol)3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol was added. Theresulting solution was maintained at room temperature for 3 days. Themixture was added onto a NaHCO₃ aqueous solution at pH 8, and it wasextracted with dichloromethane (3×50 ml). The pooled organic extractswere dried over Na₂SO₄, then filtered and concentrated at reducedpressure. The resulting residue was purified by column chromatography onsilica gel (eluent: dichloromethane/acetone 9:1 and increasing amountsof acetone), whereby 12.2 g (66%) of the title compound as a white foamwere obtained.

¹H-NMR(CDCl₃): 1.20-2.20 (m, 16H) including a 2.12 (s, 6H); 2.45 (dd,1H); 6.95 (dd, 1H); 7.05 (m, 2H); 7.43 (m, 3H); 8.05 (d, 1H); 10.60 (br.s, 1H).

Example No. 4 (RR-SS)-2-Hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

Operating in a similar way to that described to prepare the compound ofExample 3 and starting from 10.0 g (65.7 mmol) 4-methylsalicylic acid,10.0 g (61.7 mmol) carbonyldiimidazole, 14.3 g (57.4 mmol)3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol and 165 ml anhydroustetrahydrofuran, and after column chromatography on silica gel (eluent:9:1 dichloromethane/acetone and increasing amounts of acetone), 14.6 g(66%) of the title compound was obtained as a white foam.

¹H-NMR(CDCl₃): 1.20-2.60 (m, 20H) including a 2.15 (s, 6H) and a 2.20(s, 3H); 6.80 (m, 2H); 7.05 (m, 1H); 7.45 (m, 3H); 7.95 (d, 1H); 10.55(s, 1H).

Example No. 5 (RR-SS)-2-Hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

Operating in a similar way to that described to prepare the compound ofExample 3 and starting from 10.0 g (59.5 mmol) 4-mehoxysalicylic acid,9.1 g (56.2 mmol) carbonyldiimidazole, 12.9 g (51.8 mmol)3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol and 150 ml anhydroustetrahydrofuran, and after column chromatography on silica gel (eluent:9:1 dichloromethane/acetone and increasing amounts of acetone), 13.7 g(66%) of the title compound was obtained as a white foam.

¹H-NMR(CDCl₃): 1.20-2.30 μm, 16H) including a 2.15 (s, 6H); 2.45 (dd,1H); 3.85 (s, 3H); 6.55 (m, 2H); 7.07 (m, 1H); 7.40 (m, 3H); 7.95 (d,1H); 10.75 (s, 1H).

Example No. 6 (RR-SS)-2-Hydroxy-5-nitro-benzoic acid3-(2dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

Operating in a similar way to that described to prepare the compound ofExample 3 and starting from 10.0 g (54.6 mmol) 5-nitrosalicylic acid,8.3 g (51.2 mmol) carbonyldiimidazole, 11.9 g (47.8 mmol)3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol and 135 ml anhydroustetrahydrofuran, and after column chromatography on silica gel (eluent:1:1 dichloromethane/acetone and increasing amounts of acetone), 326 mg(2%) of the title compound was obtained as a yellow solid.

¹H-NMR(CDCl₃): 1.20-2,30 (m, 16H) including at 2,15 (s, 6H); 2.45 (dd,1H); 7.00-7.25 (m, 2H); 7.45 (m, 3H); 8.40 (dd, 1H); 9.05 (d, 1H).

Example No. 7 (RR-SS)-2′,4′-Difluoro-3-hydroxy-biphenyl-4-carboxylicacid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester

Operating in a similar way to that described in Example 3 and startingfrom 5.0 g 2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid, 3.5 gcarbonyldiimidazole, 5.0 g3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol and 50 ml anhydroustetra-hydrofuran, and after column chromatography on silica gel, 4,1 gof the title compound was obtained as a white foam.

¹H-NMR(CDCl₃): 1.20-2.30 (m, 16H) including at 2.15 (s, 6H); 2.45 (dd,1H); 6.85-7.55 (m, 9H); 7.70 (m, 1H); 8.22 (d, 1H); 10.60 (br. s, 1H).

Pharmacological Results

In the following Table 1, the pharmacological activity results forseveral examples of the product of the invention are shown, as well asfor Tramadol. The results are expressed as percent increment in theresponse time in the hot plate test.

As it can be seen, the compounds of the invention present activities upto three times higher than that of tramadol.

Analgesic Activity of the Products in the Hot Plate Test in Mice

TABLE 1 PRODUCT Percent increment 80 μmol/kg p.o. response time Tramadol218 EXAMPLE 1 710 EXAMPLE 2 724 EXAMPLE 3 400 EXAMPLE 4 525 EXAMPLE 5688 EXAMPLE 6 661 EXAMPLE 7 686

1. Compound of general formula (I):

wherein: R₁ is halogen, optional substituted C₁-C₆ alkyl, OR₃, NO₂ oroptionally substituted aryl, where R₃ is C₁-C₄ alkyl, R₂ is: H or CH₃CO; and the salts and optical isomers thereof.
 2. A compound accordingto claim 1, characterized in that R₁ is halogen, such as F, Cl, Br,halosubstituted phenyl or hydro (C₁-C₆ fluoroalky).
 3. Compound asclaimed in claim 1, characterized in that it is selected from one of thefollowing: (RR-SS)-2-Acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester;(RR-SS)-2-Hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester;(RR-SS)-4-Chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester;(RR-SS)-2-Hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester;(RR-SS)-2-Hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester;(RR-SS)-2-Hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester; (RR-SS)-2′,4-Difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester.
 4. Aprocess for obtaining a compound of general formula (I):

as claimed in claim 1, characterised in that a compound of formula (II);

is reacted with a compound of general formula (III);

wherein R₁y R₂ have the same meaning as above, and L=OH, halogen

O—R₄ or —CO—R₅, where R₄=C₁-C₄ alkyl, phenyl, optionally substitutedphenyl, and R₅=Alkyl, a phenyl ring optionally substituted with one ormore substituents, or a heterocyclic ring optionally substituted withone or more substituents, in an inert solvent, at temperatures rangingfrom −20° C. to 120° C.
 5. A process according to claim 4, characterizedin that a condensation promoting agent is added.
 6. A process accordingto claim 4, characterized in that said inert solvent is selected fromdichloromethane, tetrahydrofuran, acetonitrile, 1,2-dichloroethane,ethyl acetate, dimethoxyethane or dioxane, preferably dichloromethane ortetrahydrofuran.
 7. A process according to claim 5, characterized inthat said condensation promoting agent is selected fromcarbonyldiimidazole, dicyclohexylcarbodiimide, triethylamineethylchloroformate, triethylamine benzotriazoletosylate ordiethylchlorophosphate, preferably carbonyldiimidazole ordicyclohexylcarbodiimide.
 8. A process according to claim 4,characterized in that said temperature range is from 0° and 35° C.
 9. Amethod for treatment of pain which comprises administering to a humanbeing in need of said treatment an effective dose of a compound ofgeneral formula (I) according to claim
 1. 10. A pharmaceuticalcomposition, which comprises a compound of general formula (I) accordingto claim 1 and a pharmaceutically acceptable excipient, for thetreatment of pain.